SummaryMultiferroics (i.e. materials where ferroelectricity and magnetism coexist) are presently drawing enormous interests, due to their technologically-relevant multifunctional character and to the astoundingly rich playground for fundamental condensed-matter physics they constitute. Here, we put forward several concepts on how to break inversion symmetry and achieve sizable ferroelectricity in collinear magnets; our approach is corroborated via first-principles calculations as tools to quantitatively estimate relevant ferroelectric and magnetic properties as well as to reveal ab-initio the main mechanisms behind the dipolar and magnetic orders. In closer detail, we focus on the interplay between ferroelectricity and electronic degrees of freedom in magnets, i.e. on those cases where spin- or orbital- or charge-ordering can be the driving force for a spontaneous polarization to develop. Antiferromagnetism will be considered as a primary mechanism for lifting inversion symmetry; however, the effects of charge disproportionation and orbital ordering will also be studied by examining a wide class of materials, including ortho-manganites with E-type spin-arrangement, non-E-type antiferromagnets, nickelates, etc. Finally, as an example of materials-design accessible to our ab-initio approach, we use “chemistry” to break inversion symmetry by artificially constructing an oxide superlattice and propose a way to switch, via an electric field, from antiferromagnetism to ferrimagnetism. To our knowledge, the link between electronic degrees of freedom and ferroelectricity in collinear magnets is an almost totally unexplored field by ab-initio methods; indeed, its clear understanding and optimization would lead to a scientific breakthrough in the multiferroics area. Technologically, it would pave the way to materials design of magnetic ferroelectrics with properties persisting above room temperature and, therefore, to a novel generation of electrically-controlled spintronic devices

Multiferroics (i.e. materials where ferroelectricity and magnetism coexist) are presently drawing enormous interests, due to their technologically-relevant multifunctional character and to the astoundingly rich playground for fundamental condensed-matter physics they constitute. Here, we put forward several concepts on how to break inversion symmetry and achieve sizable ferroelectricity in collinear magnets; our approach is corroborated via first-principles calculations as tools to quantitatively estimate relevant ferroelectric and magnetic properties as well as to reveal ab-initio the main mechanisms behind the dipolar and magnetic orders. In closer detail, we focus on the interplay between ferroelectricity and electronic degrees of freedom in magnets, i.e. on those cases where spin- or orbital- or charge-ordering can be the driving force for a spontaneous polarization to develop. Antiferromagnetism will be considered as a primary mechanism for lifting inversion symmetry; however, the effects of charge disproportionation and orbital ordering will also be studied by examining a wide class of materials, including ortho-manganites with E-type spin-arrangement, non-E-type antiferromagnets, nickelates, etc. Finally, as an example of materials-design accessible to our ab-initio approach, we use “chemistry” to break inversion symmetry by artificially constructing an oxide superlattice and propose a way to switch, via an electric field, from antiferromagnetism to ferrimagnetism. To our knowledge, the link between electronic degrees of freedom and ferroelectricity in collinear magnets is an almost totally unexplored field by ab-initio methods; indeed, its clear understanding and optimization would lead to a scientific breakthrough in the multiferroics area. Technologically, it would pave the way to materials design of magnetic ferroelectrics with properties persisting above room temperature and, therefore, to a novel generation of electrically-controlled spintronic devices

Max ERC Funding

684 000 €

Duration

Start date: 2008-05-01, End date: 2012-04-30

Project acronymBODY-OWNERSHIP

ProjectNeural mechanisms of body ownership and the projection of ownership onto artificial bodies

Researcher (PI)H. Henrik Ehrsson

Host Institution (HI)KAROLINSKA INSTITUTET

Call DetailsStarting Grant (StG), LS4, ERC-2007-StG

SummaryHow do we recognize that our limbs are part of our own body, and why do we feel that one’s self is located inside the body? These fundamental questions have been discussed in theology, philosophy and psychology for millennia. The aim of my ground-breaking research programme is to identify the neuronal mechanisms that produce the sense of ownership of the body, and the processes responsible for the feeling that the self is located inside the physical body. To solve these questions I will adopt an inter-disciplinary approach using state-of-the-art methods from the fields of imaging neuroscience, experimental psychology, computer science and robotics. My first hypothesis is that the mechanism for body ownership is the integration of information from different sensory modalities (vision, touch and muscle sense) in multi-sensory brain areas (ventral premotor and intraparietal cortex). My second hypothesis is that the sense of where you are located in the environment is mediated by allocentric spatial representations in medial temporal lobes. To test this, I will use perceptual illusions and virtual-reality techniques that allow me to manipulate body ownership and the perceived location of the self, in conjunction with non-invasive recordings of brain activity in healthy humans. Functional magnetic resonance imaging and electroencephalography will be used to identify the neuronal correlates of ownership and ‘in-body experiences’, while transcranial magnetic stimulation will be used to examine the causal relationship between neural activity and ownership. It is no overstatement to say that my pioneering work could define a new sub-field in cognitive neuroscience dealing with how the brain represents the self. These basic scientific discoveries will be used in new frontier applications. For example, the development of a prosthetic limb that feels just like a real limb, and a method of controlling humanoid robots by the illusion of ‘becoming the robot’.

How do we recognize that our limbs are part of our own body, and why do we feel that one’s self is located inside the body? These fundamental questions have been discussed in theology, philosophy and psychology for millennia. The aim of my ground-breaking research programme is to identify the neuronal mechanisms that produce the sense of ownership of the body, and the processes responsible for the feeling that the self is located inside the physical body. To solve these questions I will adopt an inter-disciplinary approach using state-of-the-art methods from the fields of imaging neuroscience, experimental psychology, computer science and robotics. My first hypothesis is that the mechanism for body ownership is the integration of information from different sensory modalities (vision, touch and muscle sense) in multi-sensory brain areas (ventral premotor and intraparietal cortex). My second hypothesis is that the sense of where you are located in the environment is mediated by allocentric spatial representations in medial temporal lobes. To test this, I will use perceptual illusions and virtual-reality techniques that allow me to manipulate body ownership and the perceived location of the self, in conjunction with non-invasive recordings of brain activity in healthy humans. Functional magnetic resonance imaging and electroencephalography will be used to identify the neuronal correlates of ownership and ‘in-body experiences’, while transcranial magnetic stimulation will be used to examine the causal relationship between neural activity and ownership. It is no overstatement to say that my pioneering work could define a new sub-field in cognitive neuroscience dealing with how the brain represents the self. These basic scientific discoveries will be used in new frontier applications. For example, the development of a prosthetic limb that feels just like a real limb, and a method of controlling humanoid robots by the illusion of ‘becoming the robot’.

Max ERC Funding

909 850 €

Duration

Start date: 2008-12-01, End date: 2013-11-30

Project acronymBRAINPLASTICITY

ProjectIn vivo imaging of functional plasticity in the mammalian brain

Researcher (PI)Adi Mizrahi

Host Institution (HI)THE HEBREW UNIVERSITY OF JERUSALEM

Call DetailsStarting Grant (StG), LS4, ERC-2007-StG

Summary"The dynamic nature of the brain operates at disparate time scales ranging from milliseconds to months. How do single neurons change over such long time scales? This question remains stubborn to answer in the field of brain plasticity mainly because of limited tools to study the physiology of single neurons over time in the complex environment of the brain. The research aim of this proposal is to reveal the physiological changes of single neurons in the mammalian brain over disparate time scales using time-lapse optical imaging. Specifically, we aim to establish a new team that will develop genetic and optical tools to probe the physiological activity of single neurons, in vivo. As a model system, we will study a unique neuronal population in the mammalian brain; the adult-born local neurons in the olfactory bulb. These neurons have tremendous potential to reveal how neurons develop and maintain in the intact brain because they are accessible both genetically and optically. By following the behavior of adult-born neurons in vivo we will discover how neurons mature and maintain over days and weeks. If our objectives will be met, this study has the potential to significantly ""raise the bar"" on how neuronal plasticity is studied and reveal some basic secrets of the ever changing mammalian brain."

"The dynamic nature of the brain operates at disparate time scales ranging from milliseconds to months. How do single neurons change over such long time scales? This question remains stubborn to answer in the field of brain plasticity mainly because of limited tools to study the physiology of single neurons over time in the complex environment of the brain. The research aim of this proposal is to reveal the physiological changes of single neurons in the mammalian brain over disparate time scales using time-lapse optical imaging. Specifically, we aim to establish a new team that will develop genetic and optical tools to probe the physiological activity of single neurons, in vivo. As a model system, we will study a unique neuronal population in the mammalian brain; the adult-born local neurons in the olfactory bulb. These neurons have tremendous potential to reveal how neurons develop and maintain in the intact brain because they are accessible both genetically and optically. By following the behavior of adult-born neurons in vivo we will discover how neurons mature and maintain over days and weeks. If our objectives will be met, this study has the potential to significantly ""raise the bar"" on how neuronal plasticity is studied and reveal some basic secrets of the ever changing mammalian brain."

Max ERC Funding

1 750 000 €

Duration

Start date: 2008-08-01, End date: 2013-07-31

Project acronymCAAXPROCESSINGHUMDIS

ProjectCAAX Protein Processing in Human DIsease: From Cancer to Progeria

Researcher (PI)Martin Olof Bergö

Host Institution (HI)GOETEBORGS UNIVERSITET

Call DetailsStarting Grant (StG), LS6, ERC-2007-StG

SummaryMy objective is to understand the physiologic and medical importance of the posttranslational processing of CAAX proteins (e.g., K-RAS and prelamin A) and to define the suitability of the CAAX protein processing enzymes as therapeutic targets for the treatment of cancer and progeria. CAAX proteins undergo three posttranslational processing steps at a carboxyl-terminal CAAX motif. These processing steps, which are mediated by four different enzymes (FTase, GGTase-I, RCE1, and ICMT), increase the hydrophobicity of the carboxyl terminus of the protein and thereby facilitate interactions with membrane surfaces. Somatic mutations in K-RAS deregulate cell growth and are etiologically involved in the pathogenesis of many forms of cancer. A mutation in prelamin A causes Hutchinson-Gilford progeria syndrome—a pediatric progeroid syndrome associated with misshaped cell nuclei and a host of aging-like disease phenotypes. One strategy to render the mutant K-RAS and prelamin A less harmful is to interfere with their ability to bind to membrane surfaces (e.g., the plasma membrane and the nuclear envelope). This could be accomplished by inhibiting the enzymes that modify the CAAX motif. My Specific Aims are: (1) To define the suitability of the CAAX processing enzymes as therapeutic targets in the treatment of K-RAS-induced lung cancer and leukemia; and (2) To test the hypothesis that inactivation of FTase or ICMT will ameliorate disease phenotypes of progeria. I have developed genetic strategies to produce lung cancer or leukemia in mice by activating an oncogenic K-RAS and simultaneously inactivating different CAAX processing enzymes. I will also inactivate several CAAX processing enzymes in mice with progeria—both before the emergence of phenotypes and after the development of advanced disease phenotypes. These experiments should reveal whether the absence of the different CAAX processing enzymes affects the onset, progression, or regression of cancer and progeria.

My objective is to understand the physiologic and medical importance of the posttranslational processing of CAAX proteins (e.g., K-RAS and prelamin A) and to define the suitability of the CAAX protein processing enzymes as therapeutic targets for the treatment of cancer and progeria. CAAX proteins undergo three posttranslational processing steps at a carboxyl-terminal CAAX motif. These processing steps, which are mediated by four different enzymes (FTase, GGTase-I, RCE1, and ICMT), increase the hydrophobicity of the carboxyl terminus of the protein and thereby facilitate interactions with membrane surfaces. Somatic mutations in K-RAS deregulate cell growth and are etiologically involved in the pathogenesis of many forms of cancer. A mutation in prelamin A causes Hutchinson-Gilford progeria syndrome—a pediatric progeroid syndrome associated with misshaped cell nuclei and a host of aging-like disease phenotypes. One strategy to render the mutant K-RAS and prelamin A less harmful is to interfere with their ability to bind to membrane surfaces (e.g., the plasma membrane and the nuclear envelope). This could be accomplished by inhibiting the enzymes that modify the CAAX motif. My Specific Aims are: (1) To define the suitability of the CAAX processing enzymes as therapeutic targets in the treatment of K-RAS-induced lung cancer and leukemia; and (2) To test the hypothesis that inactivation of FTase or ICMT will ameliorate disease phenotypes of progeria. I have developed genetic strategies to produce lung cancer or leukemia in mice by activating an oncogenic K-RAS and simultaneously inactivating different CAAX processing enzymes. I will also inactivate several CAAX processing enzymes in mice with progeria—both before the emergence of phenotypes and after the development of advanced disease phenotypes. These experiments should reveal whether the absence of the different CAAX processing enzymes affects the onset, progression, or regression of cancer and progeria.

Max ERC Funding

1 689 600 €

Duration

Start date: 2008-06-01, End date: 2013-05-31

Project acronymCAJS

ProjectThe Christian Appropriation of the Jewish Scriptures: Allegory, Pauline Exegesis, and the Negotiation of Religious Identities

Researcher (PI)Hagit Amirav

Host Institution (HI)STICHTING VU

Call DetailsStarting Grant (StG), SH4, ERC-2007-StG

SummaryThis project focuses on the appropriation of the Old Testament by early Christian interpreters of the Bible. A historical approach, not commonly adopted in the study of biblical interpretation, will enable us to study how this process contributed to the formation of distinctive Christian identities within the multicultural society of the late Roman principate and early Byzantine rule. The exegetes of this period were to a great extent responsible for the creation of a distinctive, sophisticated, and uncompromising discourse—a ‘totalising Christian discourse’, which determines Christian identities up to this day. In two projects, carried out by three researchers, we will make cross sections of the relevant material. It was allegorizing interpretation that enabled exegetes belonging to the so-called School of Alexandria to recognize Christ everywhere in the Old Testament, and thus to appropriate it and make it useful to the Church. Thus the Song of Songs was no longer considered an earthly love song, but was said to describe Christ’s love for the Church. Exegetes associated with the School of Antioch opposed to this kind of approach. They are often described as literalists. The traditional understanding of the distinctions between the two schools needs to be broadened and corrected by a picture of the actual practice of their hermeneutics. In my view the Antiochene opposition was brought about by the fact that pagan and ‘heretic’ critics did not accept the Alexandrian use of allegory. My innovative hypothesis is related to the central role played by the letters of the apostle Paul in the Antiochene reaction against Alexandria. For the Antiochenes, the use of Paul became an alternative means to bridge the gap between the two Testaments. Instead of a book in which every jot and tittle referred to Christ through allegory, the Antiochenes came to view the Old Testament as an amalgamation of moral lessons that agreed with Paul's teaching.

This project focuses on the appropriation of the Old Testament by early Christian interpreters of the Bible. A historical approach, not commonly adopted in the study of biblical interpretation, will enable us to study how this process contributed to the formation of distinctive Christian identities within the multicultural society of the late Roman principate and early Byzantine rule. The exegetes of this period were to a great extent responsible for the creation of a distinctive, sophisticated, and uncompromising discourse—a ‘totalising Christian discourse’, which determines Christian identities up to this day. In two projects, carried out by three researchers, we will make cross sections of the relevant material. It was allegorizing interpretation that enabled exegetes belonging to the so-called School of Alexandria to recognize Christ everywhere in the Old Testament, and thus to appropriate it and make it useful to the Church. Thus the Song of Songs was no longer considered an earthly love song, but was said to describe Christ’s love for the Church. Exegetes associated with the School of Antioch opposed to this kind of approach. They are often described as literalists. The traditional understanding of the distinctions between the two schools needs to be broadened and corrected by a picture of the actual practice of their hermeneutics. In my view the Antiochene opposition was brought about by the fact that pagan and ‘heretic’ critics did not accept the Alexandrian use of allegory. My innovative hypothesis is related to the central role played by the letters of the apostle Paul in the Antiochene reaction against Alexandria. For the Antiochenes, the use of Paul became an alternative means to bridge the gap between the two Testaments. Instead of a book in which every jot and tittle referred to Christ through allegory, the Antiochenes came to view the Old Testament as an amalgamation of moral lessons that agreed with Paul's teaching.

SummaryCancer progression, characterized by uncontrolled proliferation and motility of cells, is a complex and deadly process. Integrins, a major cell surface adhesion receptor family, are transmembrane proteins known to regulate cell behaviour by transducing extracellular signals to cytoplasmic protein complexes. We and others have shown that recruitment of specific protein complexes by the cytoplasmic domains of integrins is important in tumorigenesis. Here our aim is to study three interrelated processes in cancer progression which involve integrin signalling, but which have not been elucidated earlier at all. 1) Integrins in cell division (cytokinesis). Since coordinated action of the cytoskeleton and membranes is needed both for cell division and motility, shared integrin functions can regulate both events. 2) Dynamic integrin signalosomes at the leading edge of invading cells. Spatially and temporally regulated, integrin-protein complexes at the front of infiltrating cells are likely to dictate the movement of cancer cells in tissues. 3) Transmembrane segments of integrins as scaffolds for integrin signalling. In addition to cytosolic proteins, integrins most likely interact with proteins within the membrane resulting into new signalling modalities. In this proposal we will use innovative, modern and even unconventional techniques (such as RNAi and live-cell arrays detecting integrin traffic, cell motility and multiplication, laser-microdissection, proteomics and bacterial-two-hybrid screens) to unravel these new integrin functions, for which we have preliminary evidence. Each project will give fundamentally novel mechanistic insight into the role of integrins in cancer. Moreover, these interdisciplinary new openings will increase our understanding in cancer progression in general and will open new possibilities for therapeutic intervention targeting both cancer proliferation and dissemination in the body.

Cancer progression, characterized by uncontrolled proliferation and motility of cells, is a complex and deadly process. Integrins, a major cell surface adhesion receptor family, are transmembrane proteins known to regulate cell behaviour by transducing extracellular signals to cytoplasmic protein complexes. We and others have shown that recruitment of specific protein complexes by the cytoplasmic domains of integrins is important in tumorigenesis. Here our aim is to study three interrelated processes in cancer progression which involve integrin signalling, but which have not been elucidated earlier at all. 1) Integrins in cell division (cytokinesis). Since coordinated action of the cytoskeleton and membranes is needed both for cell division and motility, shared integrin functions can regulate both events. 2) Dynamic integrin signalosomes at the leading edge of invading cells. Spatially and temporally regulated, integrin-protein complexes at the front of infiltrating cells are likely to dictate the movement of cancer cells in tissues. 3) Transmembrane segments of integrins as scaffolds for integrin signalling. In addition to cytosolic proteins, integrins most likely interact with proteins within the membrane resulting into new signalling modalities. In this proposal we will use innovative, modern and even unconventional techniques (such as RNAi and live-cell arrays detecting integrin traffic, cell motility and multiplication, laser-microdissection, proteomics and bacterial-two-hybrid screens) to unravel these new integrin functions, for which we have preliminary evidence. Each project will give fundamentally novel mechanistic insight into the role of integrins in cancer. Moreover, these interdisciplinary new openings will increase our understanding in cancer progression in general and will open new possibilities for therapeutic intervention targeting both cancer proliferation and dissemination in the body.

Max ERC Funding

1 529 369 €

Duration

Start date: 2008-08-01, End date: 2013-07-31

Project acronymCANCERSTEM

ProjectStem cells in epithelial cancer initiation and growth

Researcher (PI)Cédric Blanpain

Host Institution (HI)UNIVERSITE LIBRE DE BRUXELLES

Call DetailsStarting Grant (StG), LS6, ERC-2007-StG

SummaryCancer is the result of a multi-step process requiring the accumulation of mutations in several genes. For most cancers, the target cells of oncogenic mutations are unknown. Adult stem cells (SCs) might be the initial target cells as they self-renew for extended periods of time, providing increased opportunity to accumulate the mutations required for cancer formation. Certain cancers contain cells characteristics of SC with high self-renewal capacities and the ability to reform the parental tumor upon transplantation. However, whether the initial oncogenic mutations arise in normal stem cells or in more differentiated cells that re-acquire stem cell-like properties remains to be determined. The demonstration that SCs are the target cells of the initial transforming events and that cancers contain cells with SC characteristics await the development of tools allowing for the isolation and characterization of normal adult SCs. In most epithelia from which cancers naturally arise, such tools are not yet available. We have recently developed novel methods to specifically mark and isolate multipotent epidermal slow-cycling SCs, making it now possible to determine the role of SC during epithelial cancer formation. In this project, we will use mice epidermis as a model to define the role of SC in epithelial cancer initiation and growth. Specifically, we will determine whether epithelial SCs are the initial target cells of oncogenic mutations during skin cancer formation, whether oncogenic mutations lead preferentially to skin cancer when they arise in SC rather than in more committed cells and whether cancer stem cells contribute to epithelial tumor growth and relapse after therapy.

Cancer is the result of a multi-step process requiring the accumulation of mutations in several genes. For most cancers, the target cells of oncogenic mutations are unknown. Adult stem cells (SCs) might be the initial target cells as they self-renew for extended periods of time, providing increased opportunity to accumulate the mutations required for cancer formation. Certain cancers contain cells characteristics of SC with high self-renewal capacities and the ability to reform the parental tumor upon transplantation. However, whether the initial oncogenic mutations arise in normal stem cells or in more differentiated cells that re-acquire stem cell-like properties remains to be determined. The demonstration that SCs are the target cells of the initial transforming events and that cancers contain cells with SC characteristics await the development of tools allowing for the isolation and characterization of normal adult SCs. In most epithelia from which cancers naturally arise, such tools are not yet available. We have recently developed novel methods to specifically mark and isolate multipotent epidermal slow-cycling SCs, making it now possible to determine the role of SC during epithelial cancer formation. In this project, we will use mice epidermis as a model to define the role of SC in epithelial cancer initiation and growth. Specifically, we will determine whether epithelial SCs are the initial target cells of oncogenic mutations during skin cancer formation, whether oncogenic mutations lead preferentially to skin cancer when they arise in SC rather than in more committed cells and whether cancer stem cells contribute to epithelial tumor growth and relapse after therapy.

Max ERC Funding

1 600 000 €

Duration

Start date: 2008-07-01, End date: 2013-12-31

Project acronymCARBENZYMES

ProjectProbing the relevance of carbene binding motifs in enzyme reactivity

Researcher (PI)Martin Albrecht

Host Institution (HI)UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN

Call DetailsStarting Grant (StG), PE4, ERC-2007-StG

SummaryHistidine (His) is an ubiquitous ligand in the active site of metalloenzymes that is assumed by default to bind the metal center through one of its nitrogen atoms. However, protonation of His, which is likely to occur in locally slightly acidic environment, gives imidazolium sites that can bind a metal in a carbene-type structure as found in N-heterocyclic carbene complexes. Such carbene bonding has a dramatic effect on the properties of the metal center and may provide a rational for the mode of action of metalloenzymes that are still lacking a solid understanding. Up to now, the possibility of carbene bonding has been completely overlooked. Hence, any evidence for such His coordination via carbon will induce a shift of paradigm in classical peptide chemistry and will be directly included in basic textbooks. Moreover, this unprecedented bonding mode will provide access to unique and hitherto unknown reactivity patterns for artificial enzyme mimics. Undoubtedly, such a break-through will set a new stage in modern metalloenzyme research. A multicentered approach is proposed to identify for the first time carbene bonding in enzymes. This approach unconventionally combines the current frontiers of organometallic and biochemical knowledge and hence crosses traditional boarders. Specifically, we aim at probing carbene bonding of His by identifying reactivity patterns that are selective for metal-carbenes but not for metal-imine complexes. This will allow for efficient screening of large classes of metalloenzymes. In parallel, active site models will be constructed in which the His ligand is substituted by a heterocyclic carbene as a rigidly C-bonding His analog. For this purpose chemical synthesis will be considered as well as enzyme mutagenesis and subsequent carbene coordination. While such new bioorganometallic entities will be highly attractive to probe the influence of C-bound His on the metal site, they also provide conceputally new types of versatile catalysts.

Histidine (His) is an ubiquitous ligand in the active site of metalloenzymes that is assumed by default to bind the metal center through one of its nitrogen atoms. However, protonation of His, which is likely to occur in locally slightly acidic environment, gives imidazolium sites that can bind a metal in a carbene-type structure as found in N-heterocyclic carbene complexes. Such carbene bonding has a dramatic effect on the properties of the metal center and may provide a rational for the mode of action of metalloenzymes that are still lacking a solid understanding. Up to now, the possibility of carbene bonding has been completely overlooked. Hence, any evidence for such His coordination via carbon will induce a shift of paradigm in classical peptide chemistry and will be directly included in basic textbooks. Moreover, this unprecedented bonding mode will provide access to unique and hitherto unknown reactivity patterns for artificial enzyme mimics. Undoubtedly, such a break-through will set a new stage in modern metalloenzyme research. A multicentered approach is proposed to identify for the first time carbene bonding in enzymes. This approach unconventionally combines the current frontiers of organometallic and biochemical knowledge and hence crosses traditional boarders. Specifically, we aim at probing carbene bonding of His by identifying reactivity patterns that are selective for metal-carbenes but not for metal-imine complexes. This will allow for efficient screening of large classes of metalloenzymes. In parallel, active site models will be constructed in which the His ligand is substituted by a heterocyclic carbene as a rigidly C-bonding His analog. For this purpose chemical synthesis will be considered as well as enzyme mutagenesis and subsequent carbene coordination. While such new bioorganometallic entities will be highly attractive to probe the influence of C-bound His on the metal site, they also provide conceputally new types of versatile catalysts.

SummaryWith this proposal the PI capitalises on his recent breakthroughs in transition metal catalysed carbene (migratory) insertion reactions to build up a new research line for controlled catalytic preparation of a variety of new functionalised (co)polymers with expected special material properties. Metallo-carbenes are well-known intermediates in olefin cyclopropanation and olefin metathesis, but the PI recently discovered that their chemistry is far richer. He demonstrated for the first time that metallo-carbenoids can be used in transition metal catalysed insertion polymerisation to arrive at completely new types of stereoregular carbon-chain polymers functionalised at each carbon of the polymer backbone. Rhodium mediated polymerisation of carbenes provides the means to prepare new materials with yet unknown properties. It also provides a valuable alternative to prepare practically identical polymers as in the desirable (but still unachievable) highly stereo-selective (co)polymerisation of functionalised olefins, representing the ‘holey-grail’ in world-wide TM polymerisation catalysis research. The mechanism and scope of this remarkable new discovery will be investigated and new, improved catalysts will be developed for the preparation of novel materials based on homo- and copolymerisation of a variety of carbene precursors. Copolymerisation of carbenes and other reactive monomers will also be investigated and the properties of all new materials will be investigated. In addition the team will try to uncover new reactions in which carbene insertion reactions play a central role. DFT calculations suggest that the transition state (TS) of the new carbene polymerisation reaction is very similar to the TS’s of a variety of carbonyl insertion reactions. Based on this analogy, the team will investigate several new carbene insertion reactions, potentially leading to new, useful polymeric materials and new synthetic routes to prepare small functional organic molecules.

With this proposal the PI capitalises on his recent breakthroughs in transition metal catalysed carbene (migratory) insertion reactions to build up a new research line for controlled catalytic preparation of a variety of new functionalised (co)polymers with expected special material properties. Metallo-carbenes are well-known intermediates in olefin cyclopropanation and olefin metathesis, but the PI recently discovered that their chemistry is far richer. He demonstrated for the first time that metallo-carbenoids can be used in transition metal catalysed insertion polymerisation to arrive at completely new types of stereoregular carbon-chain polymers functionalised at each carbon of the polymer backbone. Rhodium mediated polymerisation of carbenes provides the means to prepare new materials with yet unknown properties. It also provides a valuable alternative to prepare practically identical polymers as in the desirable (but still unachievable) highly stereo-selective (co)polymerisation of functionalised olefins, representing the ‘holey-grail’ in world-wide TM polymerisation catalysis research. The mechanism and scope of this remarkable new discovery will be investigated and new, improved catalysts will be developed for the preparation of novel materials based on homo- and copolymerisation of a variety of carbene precursors. Copolymerisation of carbenes and other reactive monomers will also be investigated and the properties of all new materials will be investigated. In addition the team will try to uncover new reactions in which carbene insertion reactions play a central role. DFT calculations suggest that the transition state (TS) of the new carbene polymerisation reaction is very similar to the TS’s of a variety of carbonyl insertion reactions. Based on this analogy, the team will investigate several new carbene insertion reactions, potentially leading to new, useful polymeric materials and new synthetic routes to prepare small functional organic molecules.

Max ERC Funding

1 250 000 €

Duration

Start date: 2008-08-01, End date: 2013-07-31

Project acronymCDNF

ProjectCompartmentalization and dynamics of Nuclear functions

Researcher (PI)Angela Taddei

Host Institution (HI)INSTITUT CURIE

Call DetailsStarting Grant (StG), LS2, ERC-2007-StG

SummaryThe eukaryotic genome is packaged into large-scale chromatin structures that occupy distinct domains in the nucleus and this organization is now seen as a key contributor to genome functions. Two key functions of the genome can take advantage of nuclear organization: regulated gene expression and the propagation of a stable genome. To understand these fundamental processes, we have chosen to use yeast as a model system that allows genetics, molecular biology and advanced live microscopy approaches to be combined. Budding yeast have been very powerful to demonstrate that gene position can play an active role in regulating gene expression. Distinct subcompartments dedicated to either gene silencing or activation of specific genes are positioned at the nuclear periphery. To gain insight into the mechanisms underlying this sub-compartmentalization, we will address three complementary issues: - What are the mechanisms involved in the establishment and maintenance of silent nuclear compartments? - How and why are some activated genes recruited to the nuclear periphery? - What are the relationships between repressive and activating nuclear compartments? Concerning the maintenance of genome integrity, recent advances in yeast highlight the importance of nuclear architecture. However, how nuclear organization influences the formation and processing of DNA lesions remain poorly understood. We will focus on two main questions: - How and where in the nucleus are double strand breaks recognized, processed, and repaired? - Where do breaks or gaps resulting from replicative stress at 'fragile sites' arise in the nucleus and how does nuclear organization influence their stability? We hope to gain a better understanding of the mechanisms presiding nuclear organization and its importance for genome functions. These mechanisms are likely to be conserved and will be subsequently tested in higher eukaryotic cells.

The eukaryotic genome is packaged into large-scale chromatin structures that occupy distinct domains in the nucleus and this organization is now seen as a key contributor to genome functions. Two key functions of the genome can take advantage of nuclear organization: regulated gene expression and the propagation of a stable genome. To understand these fundamental processes, we have chosen to use yeast as a model system that allows genetics, molecular biology and advanced live microscopy approaches to be combined. Budding yeast have been very powerful to demonstrate that gene position can play an active role in regulating gene expression. Distinct subcompartments dedicated to either gene silencing or activation of specific genes are positioned at the nuclear periphery. To gain insight into the mechanisms underlying this sub-compartmentalization, we will address three complementary issues: - What are the mechanisms involved in the establishment and maintenance of silent nuclear compartments? - How and why are some activated genes recruited to the nuclear periphery? - What are the relationships between repressive and activating nuclear compartments? Concerning the maintenance of genome integrity, recent advances in yeast highlight the importance of nuclear architecture. However, how nuclear organization influences the formation and processing of DNA lesions remain poorly understood. We will focus on two main questions: - How and where in the nucleus are double strand breaks recognized, processed, and repaired? - Where do breaks or gaps resulting from replicative stress at 'fragile sites' arise in the nucleus and how does nuclear organization influence their stability? We hope to gain a better understanding of the mechanisms presiding nuclear organization and its importance for genome functions. These mechanisms are likely to be conserved and will be subsequently tested in higher eukaryotic cells.